Protein kinases catalyze the transfer of the terminal phosphate from ATP or GTP to the hydroxyl group of tyrosine, serine and/or threonine residues of proteins. Protein kinases are categorized into families by the substrates they phosphorylate, for example, protein tyrosine kinases (PTK), and protein serine/threonine kinases. Phosphorylation via protein kinase(s) results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location or association with other proteins. Protein kinases play vital role in variety of cellular processes; cell proliferation, cell survival, metabolism, carbohydrate utilization, protein synthesis, angiogenesis, cell growth and immune response.
Misregulation of the protein kinases has been implicated in numerous diseases and disorders such as central nervous system disorders (e.g., Alzheimer's disease), inflammatory and autoimmune disorders (e.g., asthma, rheumatoid arthritis, Crohn's disease, and inflammatory bowel syndrome, and psoriasis), bone diseases (e.g., osteoporosis), metabolic disorders (e.g., diabetes), blood vessel proliferative disorders, ocular diseases, cardiovascular disease, cancer, restenosis, pain sensation, transplant rejection and infectious diseases.
Among them, overexpression and misregulation of EGFR is commonly found in breast, lung, pancreas, head and neck, as well as bladder tumors. EGFR is a transmembrane protein tyrosine kinase member of the erbB receptor family. Upon binding of a growth factor ligand such as epidermal growth factor (EGF), the receptor can dimerize with EGFR or with another family member such as erbB2 (HER2), erbB3 (HER3) and erbB4 (HER4). The dimerization of erbB receptors leads to the phosphorylation of key tyrosine residues in the intracellular domain and sequentially to stimulation of numerous intracellular signal transduction pathways involved in cell proliferation and survival. Misregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor survival and has been described in many human cancers such as lung and breast.
Therefore, the erbB family is a rational target for anticancer drug development and a number of compounds targeting EGFR or erbB2 are now clinically available, including gefitinib (IRESSA™) and erlotinib (TARCEVA™), the first generation inhibitor. It was reported that the most common EGFR activating mutations, L858R and del E746-A750 were sensitive to treatment of gefitinib or erlotinib but ultimately acquired resistance to therapy with gefitinib or erlotinib arises predominantly by mutation of the gatekeeper residue T790M, which is detected in approximately half of clinically resistant patients, resulting in double mutants, L858R/T790M and del E746-A750/T790M.
Biological and clinical importance of EGFR mutants has been recognized in the field and several second generation drugs such as BIBW2992 (Afatinib), HKI-272 and PF0299804 are in development and effective against the T790M resistance mutation but show concurrent strong inhibition of wildtype (WT) EGFR, which causes severe adverse effect. Therefore, a strong need still exists for compounds which potently inhibit EGFR single and double mutants as well as are selective over WT EGFR to provide an effective and safe clinical therapy for the diseases associated with or mediated by EGFR mutants.
Another example of misregulation of the protein kinases that has been implicated in numerous diseases and disorders is Janus kinase (JAK) 3. In contrast to the relatively ubiquitous expression of Janus family member, JAK1, JAK2 and Tyk2, JAK3 is predominantly expressed in hematopoietic lineage such as NK cells, T cells and B cells and intestinal epithelial cells. Targeting JAK3 could be a useful strategy to generate a novel class of immunosuppressant drugs. Due to primary expression in hematopoietic cells, so a highly selective JAK3 inhibitor should have precise effects on immune cells and minimal pleiotropic defects. The selectivity of a JAK3 inhibitor would also have advantages over the current widely used immunosuppressant drugs, which have abundant targets and diverse side effects. A JAK3 inhibitor could be useful for treating autoimmune diseases, and JAK3 mediated leukemia and lymphoma.
For example, somatic mutations of JAK3 were also identified in a minority of acute megakaryoblastic leukaemia (AMKL) patients both in Down syndrome children and non-Down syndrome adults, and in a patient with acute lymphoblastic leukaemia. In addition, JAK3 activation was identified in several lymphoproliferative disorders, including mantle cell lymphoma, Burkitt's lymphoma, human T-cell leukemia/lymphoma, virus-1-induced adult T-cell lymphoma/leukemia and anaplastic large cell lymphoma. It was shown that constitutive activation of the JAK3/STAT pathway has a major role in leukemia and lymphoma cell growth and survival and in the invasive phenotype. Therefore, the constitutive activation of JAK3, which can result from JAK3-activating mutations, is a frequent feature of several leukemia and lymphoma so that selective inhibition of JAK3 could be therapeutic target.
Therefore, a strong need exists for compounds which selectively and potently inhibit JAK3 wildtype and mutants as well as are selective over other JAK family members to provide an effective and safe clinical therapy for the diseases associated with or mediated by JAK3.
A need also exists for methods of administering such compounds, pharmaceutical formulations and medicaments to patients or subjects in need thereof.